In this application we propose the development of small molecule inhibitors of the HIV Vif protein. While Vif has been recognized as an important gene for viral infectivity, the cellular mechanism responsible for this effect has only recently been elucidated. Vif functions to inactivate the cellular defense protein APOBEC 3G which otherwise induces deamination of viral DNA rendering it noninfectious. Our previous work in vaccine development has demonstrated the crucial in vivo significance of Vif to viral replication in the rhesus macaque and supports the relevance of this drug target. The University of Massachusetts Medical School (UMMS) established a high throughput drug screening facility in order to identify lead compounds with activity against HIV/SIV Vif. As part of this venture, a large chemical library has been screened for anti-Vif compounds using a cell-based inhibitor screen and a number of lead compounds have been identified that have the potential to target peripheral and CNS reservoirs of HIV-1 replication and persistence. The proposed work will facilitate the further development of these Vif inhibiting agents. The application brings together a collaborative team with diverse expertise in medicinal chemistry, molecular virology, and in vivo systems to examine the clinical potential of such inhibitors. Our objective is to utilize pharmacokinetic and efficacy studies in rodent species in a lead optimization approach reserving proof-of-principal studies in nonhuman primates to the most promising drug candidates. Long term efficacy studies will allow us to examine the effect of Vif inhibitors on plasma viral load and markers of immunodeficiency as well as to evaluate the effect of drug treatment on SIV encephalitis, a lentiviral specific disease process. To accomplish these goals we propose the following specific aims: Specific aim 1: To define the pharmacokinetic and safety profile of novel Vif inhibitors in rodents and rhesus macaques. Specific aim 2: To examine the short term in vivo effect of Vif inhibitors on viral replication and cellular reservoirs in rodent and rhesus macaque models of HIV infection. Specific aim 3: To examine the efficacy of Vif inhibitors on biomarkers of CNS inflammation and morphologic evidence of CNS pathology in an SIV-macaque model of neuroAIDS.